Toxicity and drug resistance are major impediments underlying the limited therapeutic success of currently available mono-targeted therapies. One approach to address these problems is to exploit the biochemical and metabolic pathways that are reprogrammed in cancer cells to develop superior, less-toxic, and well-tolerated cancer therapies. Altered lipid metabolism is emerging as one of the hallmarks of cancer. Thus cellular lipids and enzymes involved in lipid biosynthesis may serve as promising anticancer targets. A few studies have examined lipids and their precursor-based formulations as attractive anticancer drug candidates. For example, alkylphospholipids (ALPs) exert cytotoxic effects by targeting cell membranes instead of conventional targets, such as DNA or microtubules. These ALPs affect a variety of cellular processes such as lipid raft function, PI3K/Akt signaling, phosphatidylcholine (PC) synthesis and generation of reactive oxygen species (ROS). ALP-induced modulation of lipid rafts has been found to enhance recruitment and activation of the death receptor Fas/CD95 to induce apoptosis. Lipid precursors such as omega-3 polyunsaturated fatty acids (ω-3 PUFA) have been implicated in reducing cancer risk with lower cancer prevalence in population with higher dietary intake of ω-3 PUFA. Several long chain ω-3 PUFA exhibit antiproliferative activity against multiple cancer types including colon and prostate.
Another lipid precursor, phosphoethanolamine (PhosE), has recently been a subject of active laboratory research for its anticancer role. PhosE is a biosynthetic precursor of phosphatidylethanolamine (PE) lipids, which constitute the second most abundant lipid class in cells. PhosE is synthesized in the first step of Kennedy pathway of PE lipid biosynthesis through ATP-dependent phosphorylation of monoethanolamine (Etn). See FIG. 1. PhosE has been shown to exhibit antitumor activity in various in vitro and in vivo models of cancer by affecting cell-cycle progression, angiogenesis, macrophage activation and multiple signaling pathways that induce apoptosis. PhosE inhibits murine melanoma by downregulation of Bax/Bad protein. The present inventors have surprisingly found that the key precursor with anticancer activity in the PE lipid pathway is not PhosE, but rather Etn.
In view of the limited success in addressing toxicities and drug resistance in current anticancer strategies, there is a need for effective, less-toxic and better-tolerated cancer therapies.